Tablet granulation apparatus



April 13, 1965 c. A. PAZAR ETAL 3,177,820

TABLET GRANULATION APPARATUS Filed March 27, 1961 4 Sheets-Sheet 1HVVENTOHS (VI/{E455 AKA/OLD P/IZAE 7 James AIE/VEY WIZEY BY April 13,1965 c. A. PAZAR ETAL 3,177,820

TABLET GRANULATION APPARATUS Filed March 27, 1961 4 Sheets-Sheet 2INVENTORS 0 /4215; AAAOID 242,42

JAMt'S yam/er w/u-v BY W M 7f, M,

April 13, 1965 c. A PAZAR ETAL TABLET GRANULATION APPARATUS 4Sheets-Sheet 4 Filed March 27 1961 INVENTORS CIMKLES 4/2/1010 P4ZA JAMESl/f/VE) w/u y United States Patent 3,177,821) TABLET GRANULATIONAPPARATU Charles Arnold Pazar, Glen Rock, and James Henry Wiley,Westwood, N.l., assignors to American Cyanamid Company, New York, N.Y.,a corporation of Maine Filed Mar. 27, 1961, Ser. No. 98,407 1 Claim.(Cl. l0714) This application is a continuation-in-part of our copendingapplication, Serial No. 22,876, filed April 18, 1960, entitled Method ofPreparing Tablet Granulations, now abandoned in favor of the instantapplication.

This invention relates to an improvement in preparing pharmaceuticaltablet granulations and tablets and to the products thus obtained, withparticular reference to an auger screw granulation apparatus.

Very few crystalline or powdered materials used as 4 satisfactorytabletting.

7 of relatively expensive devices arranged in sequence so, as

pharmaceutical agents can be compressed into suitable tablets onautomatic tabletting equipment in their crystalline or powdered form.

Some such powders are not self-adherent under reasonable pressures, andsome do not uniformly compact, so that any tablets produced would haveerratic weights.

The practice has developed of first preparing a granulation of thematerial with a grain-like structure suitable for compression intotablets. There are two well known general methods of preparing such agranulation, namely, the dry granulating process (which is also known asslugging) and the wet granulating process.

The dry granulating process consists of compressing the dried powderinto oversized tablets or slugs. These oversized tablets or slugs arethen broken into granules of varying sizes with concurrent production offines, that is, undesirable undersize material.

Many pharmaceutical materials cannot be formed into granules by drygranulation methods. In addition, in some cases, granules formed by drygranulation cannot be compressed to form tablets. Accordingly, a morefrequently used method for granulating a wide variety of pharmaceuticalmaterials is the wet granulating process.

The wet granulating process consists of moistening a dry powder, with orwithout the addition of an adhesive substance, until the whole isconverted into a porous, crumbly mass. The crumbly mass is then forcedthrough a screen in order to form discrete particles. After drying,these particles are further reduced in size by comrninuting andscreening. This results in the production of a large percentage ofgranules of a desired size but, unfortunately, it also results in theproduction of an appreciable quantity of undersize particles, calledfines. The most commonly used moistening agent is water, although othersolvents are well known for this purpose. It is also common practice toadd a substance such as gelatin, starch or gum acacia as binder, inorder to assist in granulating the material, and/ or improve thetabletting characteristics of the product. The dispersion of the binderin the mass is critical to the quality of both the granulation and thetablets produced therefrom. It is now known that a lack of homogeneityin the granulation, such as is obtained by conventional granulationprocesses, in part results in the release of uncoated particles as finesor dust, which is incapable of adhesion on compaction and which hascontributed significantly to the problems of tabletting.

With regard to the wet granulating process, there are two principaltechniques: (1) forming of granules without pressure by tumbling wettedmasses in suitable containers prior to screening; and (2) forming ofgranules with low or no pressure by mixing powders and liquids with theaid of stirring devices prior to screening.

In the first, it has proved extremely diflicult to granuto handle thenecessary operations one at a time in batch fashion; and a considerableamount of handlabor in the actual transfer of material from one piece ofapparatus to another, which adds to time and cost. Moreover, the 10% to20% of fine particles resulting from this technique tends to causebinding in the die, and capping and lamination.

Thus, neither of the two above-cited wet granulating techniques isentirely satisfactory. Also, complete reproducibility from batch tobatch cannot be obtained,

due to difiiculty in controlling the variables involved granuleformation. V V

The present invention is based upon the discovery that a plasticizedmass containing one or-more therapeutic materials may be readilyconverted into an excellent granulation by extruding a blended andmoistened mixture of ingredients under high pressure through a diehaving a plurality of orifices of critical dimensions so as to producestrands or strings or ribbons of the plasticized m'assQand then casehardening and drying these strands. The strands maybe cut or brokenbefore or after drying, or both. A minimum of hand labor and re-workingis required.

The throughput of an extruder is greatly increased by chilling the outersleeve of the extruder, so that the viscosity is much greater near theauger slee've,'with a consequent increase in extruison efiiciency.

Agroup of papers in Industrial and Engineering Chem-' istry for May1953, volume 45, No.5, gives some theoretical discussions for theconcepts of extrusion. The concepts for most of these papers are basedon Newtonian liquids, which the comparatively viscous. The theoreticalconcepts there set forth are based upon a working liquid which hassubstantially constant viscosity.

V In the present invention, the outer layer of the viscous liquid, orviscous material, in the extruder is chilled and thereby has a markedlyhigher viscosity, and as such the theoretical concepts based uponuniform viscosity no longer hold, and an extrusion rate increase ofseveral-fold can be obtained. As contrasted with a conventionalextrusion system in which the screw and the jacket are held at acomparatively constant temperature, an extru-' sion system can be usedwhich, under constant temperature conditions will have practically nooutput at all, and yet by chilling the jacket the output is increased tothree or four times ormore the constant temperature output, and theoutput of the auger screw approaches the theoreti cal output in whichthe auger screw is considered as having the type of volume relationshipthat would be expected for a screw operating with unrestricteddischarge, as for example, the thread volume of a screw in Wood, orother solid material. This canbe referred to as the volumetric capacityof the auger screw. Many extruders have been used in which the augersleeve has been jacketed or the anger screw itself has had temperaturecontrol passages overheating the extruded material. The present concepts1 revolve around the treatment of an extrusion concept in which theextruded material is chilled at the periphery in contact with the augersleeve, and by thus maintaining a completely nonuniform viscosity anentirely different 7 set of concepts are brought into play; The presentextruder gives excellent results with fluids which are Newr. Iceassented Apt-l3, 1965? tonian, non-Newtonian, thixotropic, andpseudo-plastic. Surprisingly high extrusion rates are obtained eventhough the clearance between the auger screw and the auger sleeve isgreater than the diameter of the extrusion orifices which would, atfirst impression, lead a casual observer to think that the slippage ofthe auger screw in the auger sleeve would be so excessive that nosuccessful extrusion would be obtained.

. Certain modifications of the apparatus will be described, followed bycertain examples of the use thereof, by way of exemplification of' thepresent invention, which is defined in the appended claim.

. Reference is made to the accompanying drawings in which: a

FIGURE 1 is a pictorial view, with parts broken away, of a jacketedfree-end extruder, with a jacketed hopper. 1 FIGURE 2 is a pictorialview, with parts broken away, of an electric heated hopper extruder,with a rifled screw chamber.

FIGURE 3 is a section, enlarged, along the axis of the auger screw ofthe extruder of FIGURE 2.

. FIGURE 4 is a partial section of an extruder, the end of the ugerscrew of which is positioned in a pilot bearing.

FIGURE 5 is a section along line 5-5 of FIGURE 4.

FIGURE 6 is a section along line 6-6 of FIGURE 4.

FIGURE 7 is a diagrammatic view of a granulation drying system, inpartial section.

FIGURE 8 is a view of a completed tablet from multicolored granules.

In the operation of our novel apparatus, pre-weighed quantities ofpowered components and granulating liquids are added continuously orincrementally to the mixing hopper 11, having the motor driven kneader12, or feed paddles, at least a portion of the mixing'hopper 11 isenclosed in a hopper temperature control jacket 13, to which steam orWater is supplied for heat control. The

resulting plasticized mass, which may contain one or more therapeuticmaterials then passes by gravity and the influence of the kneaderthrough the feeder tube 14 to the auger sleeve. 15. The plasticized massis then moved through the auger sleeve 15 to. the-discharge head 16 bythe rotating auger screw 17, which fits in the auger sleeve 15. Theplasticized massin the discharge head 16, being under great pressure byreason of the rotating auger screw 17, is extruded through the extrusionorifices 18 in the extrusion orifice plate 19. The extrusion orifices 18are preferably from about 0.0'1-inch to about 0.05- inch in diameter,but may be aslarge as 0.l'25-inch, or even larger, and are evenlydistributed in that part of the extrusion orifice plate 19 traversed bythe granulation cut-off knives 20-. The granulation cut-otf'knives '20are mounted on knife support arms 21, so that they traverse the lowersurface of the extrusion orifice plate 19, and cut the strands extrudedtherethrough into segments. The knives 20 are-preferably two in number,and revolve at such speed in relationship to the movement of the strandsof the plasticized mass being extruded that the segments, or granules,which are cut off by the knives, are from about 0.01-inch to 0.125-inchin length. The length is not necessarily the same as the diameter.

The knife'support arms 21', which carry the cut-off knives 20, areactuated from and "mounted on a gear box 27, which is positioned withrespect to the extrusion orifice plant 19 by the positioning arm 28. Theknife support arms 21 are driven by knife motor 29' by means; 65

of knife drive shaft 30 to gear box 27.

Thus, an average granule would have a radius of 0.0125-inch; a length of0.025-inch, a surface area. of about 300x10" square inches, a volume of1.2X10- cubic inches, and an area to volume ratio of approximately250: 1. tween and US. Standard mesh.

The granules, in the form of rods from about 0.01-inch to 0.05-inch indiameter, or more, and from about 0.01- inch to ODS-inch in length, ormore, then drop through Granules having these dimensions fall beandhardens the surface of the granules.

- the vertical case hardening duct 22 onto the belt conveyor 23 and arefed to a drier. The vertical case hardening duct 22 has perforations 24arranged so as to permit the transverse passage of hot air through thevertical case hardening duct 22 from drying air inlet 25 to the exhaustair duct 26.

As the granules drop through the vertical case hardening duct 22, thehot air passing transversely quickly dries This case hardening of thegranules imparts a surface hardness which results in their havingcharacteristic toughness and durability. This case hardening of thegranules also results in the production of a minimum of fines.

The granules on the drying belt may be dried sufiiciently so that theyare suitable for tabletting without further treatment. If desired, afterdrying, the granules may be coated for sustained release preparation ormixed with a lubricant to produce a granulation having modifiedproperties more suitable for compression into a particular tablet form,or several different granulations may be blended together.

As will be obvious, all materials which are to be granulated do notbehave exactly the same. Similarly, various granulation sizes aredesired for different purposes. For example, in making very fine orsmall tablets the granulation used should be comparatively small. For

larger tablets, a larger granulation may be used. The

size .of the granulation should be such that the inclusion or omissionof one single granule of the largest size does not appreciably afiectthe weight of a finished tablet. This is important in that in thetabletting process the granules are normally filled into cavities in aplate volumetrically and then dies axially compress the granules to formthe finished tablet. Because they are filled volumetrically, theaddition of the granules is in discrete portions, namely, not less thanone, granule, and if the omission or. inclusion of one granule couldhave an appreciable effect on the therapeutic dosage in a tablet, thesize of the granulation is necessarily too large. For many purposes, anaccuracy of at least 1% is desired. Accordingly, the largest granulewould have to have a Weight of not more than 1% of the weight of thefinished tablet. Where the tablets are to be made up of a blend of morethan one type of granule, as for example, where a blend of therapeuticand inert materials, or a blend of two or more therapeutic materialcontaining granules, are to be tabletted into a single tablet, the sizeof the granules must be somewhat smaller in order that, statistically,the proper weight will necessarily be obtained in each tablet, and thestatistical distribution whereby more .of one granule type may beobtained than of another is such that two or three granules of eithertype will not have sufiicient weight 'to throw off the dosage of atablet. Hence, it is usually desired that the granules be formed fromstrands which have a diameter of from about 0.0l-inch to about0.05-inch.

Where very large tablets are to be produced, as for example, in theveterinary trade where comparatively large tablets are produced for thetreatment of horses and cattle, a markedly larger granule issatisfactory. For the larger types of tablets, granulations having adiameter of up to 0.125-inch or more are satisfactory. With such largediameter granules, a somewhat longer drying time is required.

Whereas, it was above mentioned that a knife could be used to cut offthe individual strands in short segments, such that each segment had alength of the same order of magnitude of its diameter, other methods maybe used. For example, it is frequently convenient, to use no cut-offknife, and permit the strands to be extruded continuously onto a dryingbelt. Such an extrusion permits the individual strands-to lieheterogeneously on the belt with an increased spacing because of theheterogeneous scrambled characteristic of the strands which permits morerapid drying. Aftertthe strands are dry, the

strands may be broken into convenient lengths, as for example, byrunning through a screen mill or hammer mill. The type known as aFitzpatrick presently in use in the pharmaceutical industry gives asatisfactory shattering to the strands and breaks the longer strands upinto convenient size granules.

Because of the high compaction of the granules, and thorough dispersionof the binder, when the granules are run through such a shattering mill,a very small proportion of fines is obtained. The exact amount of finesdepends in part upon the granulation formula used, the degree ofmoistness, the degree of compaction, and the screen size and operatingspeed of the mill. Using reasonable values of these factors, however,the quantity of fines obtained is so small that the fines may be allowedto remain with the granules during the tabletting procedure, and nore-working is required. In fact, for many purposes, a small proportionof fines is desirable to fill in interstices and give freer flowing tothe tabletting operations. The length of the strands and the degree towhich the strands are broken into segments has an effect on theappearance of the finished tablet. Certainmodifications thereof will bedescribed below in conjunction with special appearance tablets.

The size of the strands is controlled by the size of the orifices 18 inthe orifice plate 19. Whereas it is convenient that these orifices becircular in shape, they may be ovoid, square, triangular, rectangular,star-shaped, or the like. Their effective diameter may be within thelimits of 0.0l-inch to about 0.05-inch for preferred tablettingprocedures.

The diameter, cross section, and length of the strand or strandsegments, as well as the density or bulking, which in turn is a functionof extrusion pressure and moisture content, may be varied to expresslysuit drying conditions. Rapid continuous drying-is achieved, which byhaving a belt length and speed, and air rate suitable for the dryingload, gives no fines or dust, so no dust collecting equipment isrequired. The strands can be extruded with internal holes, if desired.

Larger size strands may be comminuted. For example, strands having aminimum diameter of more than 0.125-inch may be broken in a sieve millto granules small enough for small size tablets. Such flexibility inpermissible operation is highly desirable. In modern pharmaceuticalmanufacture, it is desirable that equipment be usable on a large numberof formulations, so that rapid conversion from one formulation toanother can be made.

Whereas the extrusion orifices in the extrusion orifice plate 19 may bea drilled hole which is cylindrical throughout, it is usually moreconvenient to use a stepped configuration, or relieved hole, inaccordance with conventional practice in which tWo or three differentsized portions are used. For example, the plate may have a fewcomparatively large holes drilled part way therethrough, after whichmuch smaller holes are drilled part Way through the remaining portion ofthe plate, and then the final size hole drilled completely through. Byusing such a structure, the length of the smallest size, or extrusion,orifice is comparatively short, and accordingly a comparatively lowfriction is obtained as contrasted with the friction winch would beobtained if the extrusion orifice of say a diameter of .02-inch were notrelieved and extended through say a /2-inch extrusion orifice plate.Similarly, by having several small holes at the bottom of a single, muchlarger hole, the machine work which is required is reduced, and astronger plate can be obtained. Such configuration of extrusion platesis known to those dealing with such plates in the extrusion of plasticsor filaments, as for example in the extrusion of synthetic mono-filamentyarns for the textile trades.

The heavy mixing action of the screw in the auger sleeve gives a veryhigh shear stress and blending action or milling that more completelymixes the binder and other components, so that all solid pharmaceuticalparticles are coated with the binder, hence, the production of fineswhich do not readily compress to tablets is minimized. Additionally, theheavy mixing under compression of the granulation mix in the augersleeve by the auger screw gives a denser granulation than would beobtained where a granulation mixture is forced through a screen inaccordance with conventional practice. The effect is more like heavymulling. This increased density permits the production of tablets with ahigher final density, as Well as improving the strength of thegranulation, so that undue shattering is not obtained during a screeningor grinding operation to reduce the size and length of the strands to apreferred granulation size. Actually, the granules can be ground so thatthey will pass a sieve of smaller size than the diameter of the strandsas produced, but it is usually preferred that the strands be producedhaving a diameter less than the desired granulation size.

Fortunatelyand fortuitously, the degree of compaction of the granule canbe, in part, varied by the treatment in the mixing hopper. If the mixinghopper is sealed and evacuated, there is a minimum of air trapped in theindividual granulations; and as a result the granules are much harderand firmer than would be the case with some air trapped in them. In mostinstances, in the pharmaceutical trade it is desired that the mixinghopper be operated at approximately atmospheric pressure so that acertain amount of air is trapped in the granulation. The trappingof someair in the granulation gives a more rapid dissolution rate when thetablet is ingested by the user. It is to be stressed that neithercharacteristic is invariably desired. For some tablets, it isdesired-that air be trapped in the granulation, and a not too densetablet be obtained, so that the tablet disintegrates readily and rapidlyon ingestion releasing the medication in the tablet as rapidly asfeasible. In other instances, it is desired that the granulation be asfirm as possible, and that the tablet be compacted to as dense astructure as possible so that the tablet isdissolved a a very slow rateon ingestion which gives a delayed release tablet so that the medicamentis released to the system of the user over a longer period oftime. Mixedtypes of granules may be used so that some granules dissolve morerapidly than others, so that the tablet breaks up into fragments toincrease the active area with certain of the medicaments to be releasedrapidly, and others to be released more slowly. The choice of the rateof release, and the relative rate of release, depends upon theparticular effect desired by the administrator in a particularsituation. The versatility of the present granulation system permits awide discretionary variation which markedly contributes to thedesirability of the present granulation system.

As shown in FIGURE 1, the auger sleeve 15 is surrounded by an angersleeve cooling jacket 31. A coolant supply line 32, and a coolantdischarge line 33, supply and remove a coolant from its jacket. Althoughother fluids may be used, conveniently the coolant is water and thewater jacket is operated using cool Water. In many instances, cold Waterfrom a service supply line is adequate, particularly in Winter. In someinstances, in some areas, the water supply is too warm, and-a chilledwater is required.

The degree of chilling in part depends upon the granulation formulabeing used. With the smaller granulations which require a higherpressure for extrusion, a higher temperature differential gives betterresults. With large] extrusion orifices, particularly those over aboutODS-inch an adequate discharge may be obtained with little or nccooling, even though a higher and preferred discharge rate is obtainedwith cooling.

In operation, it is preferred that the contents of tilt mixing hopper 11be at least at room temperature, or i the therapeutic ingredientspermit, the mixture may b1 warmed up to near the boiling point of water.Heating the contents of the mixing hopper reduces the viscosit:

and permits a more thorough blending and less water in the granulation.As the mixture is fed down into the auger screw, the auger screw picksup, feeds, mills and compacts the mixture. Much effort has been spent inattempting to work out the theoretical aspects of auger operation; but,in general, the theoretical studies are limited to a single temperatureoperation, or at least one in which the temperature change was such thatthe change in viscosity did not have an appreciable effect on thetheoretical aspects of the calculations. In contradistinction thereto,it is here preferred that the cooling jacket be not higher than about 60F. and preferably down around 40 F. This chills the mixture near theperiphery so that the auger screw has a paste at a marked ly higherviscosity than that near the center of the auger sleeve. This gives achange in viscosity, and permits the auger screw-to take a bite in themixture, and gives a great increase in throughput.

When using a typical formulation with the cooling jacket inactive, acomparatively slow extrusion rate is usually obtained, and then whencooling water is admitted to the cooling jacket the extrusion rate, orthroughput, will go up to from 3 to 7 times its original value. Attimes, the change may be such that without cooling no effective amountof granulation is extruded, and yet on cooling a high throughput ispromptly obtained.

In FIGURE 2 is shown a similar extrusion device, except that the mixinghopper 34 is provided with electric block heaters 35 to supply heat tothe mixing hopper to aid in mixing the powders and liquids during thepreparations of the extrudable mass.

Also, the modification shown in FIGURE 2 does not have the casehardening duct and the extrusion from the extrusion orifice plate ispermitted to drop directly onto a drying belt, not shown, but otherwisethe structure is as in FIGURE 1.

As shown in FIGURE 3, the extruder of FIGURE 2 has a rifle grooved augersleeve. The rifle grooved auger sleeve 36 has a series of grooves 37,like the riding in a gun barrel which are either parallel to the sleeveaxis or slightly spiraled in a direction opposed to the helix of theauger screw 38 to give an improved bite of the screw on the plastic massand increase throughput. The rifle grooved auger sleeve also has anauger sleeve cooling jacket 39. In FIGURE 3, the difference intemperature of the two zones of the outer cooler mass adjacent to theauger sleeve walls, and the warmer mass adjacent to the auger screw, isshown as separated by a dotted line representing a change in thermalzones 4%).

The central shaft 41 of the auger screw 38 may have a diameter of fromabout A to of the total diameter of the auger screw. A diameter of /4 to/3 is sufiicient for stiffness and permits a larger capacity for theauger screw which, by virtue of the temperature inversion has effective,rather than merely dead, volume. The screw flight 42 should bereasonably thick inasmuch as comparatively high working stresses occurwith some granulations.

It is necessary that the auger sleeve and auger screw be made of amaterial which is corrosion resistant. Whereas experts had regardedpractically any stainless steel as satisfactory, on the basis of itscorrosion characteristics, and whereas experts had regarded theclearance on the radius as comparatively unimportant, it has developedthat galling and self-welding occurs as well as a certain amount ofburning due to the high temperature developed by friction of the screwagainst the sleeve which, in turn, gives localized overheating of thegranulation mass.

It has now been found that by using a chrome-plated screw, friction onthe screw is reduced and at the same time the tendency to galling isreduced. It is also preferred that the chamber be of a stainlessmaterial such as 316 stainless steel. With the present cooling, theclearance is not so critical so that accordingly rather than have aclearance of 0.0l-incl1 on the radius, a clearance of as 8 much. as0.029- to 0.025-inchon a radius of 2. inches gives a preferred result.It would at first be thought such a clearance would permit an undulyhigh slippage screw is unsupported, as in conventional extruderpractices, the deflection in the auger screw permits the rubbing of theauger screw against the auger sleeve.

The auger screwniay be supported at both ends. In the embodiment shownin FIGURE 4, the auger sleeve 43 is substantially cylindrical andsurrounded by an 'head to the auger sleeve.

auger sleeve cooling jacket 44, to which a coolant supply line and acoolant discharge line, not shown, conducts cooling fluid. At the rearof the auger sleeve is the auger sleeve thrust bearing 45 and the augerdrive motor 4-5; conveniently, the auger drive motor has a slotted orpolygonai adapter which positions the rear of the auger screw 47concentrically with the auger sleeve and supports the thrust developedon the auger screw.

At the'discharge end of the auger screw is the elongated discharged head48. g The elongated discharge head has a stepped flange 43-9 which fitsagainst the end of the auger sleeve 43. Bolts 59 hold the elongateddischarge It is convenient, but not necessary, that the flange have astep therein to insure that the discharge head is positioned the sameconcentrically with screw pilot bearini spider 52.

respect to the auger sleeve each time the assembly is put together. Asshown in FIGURES 4 and 5,'concentric with this flange is a spider bore51 in which fits an auger Conveniently, this spider is of X-crosssection and fits into the spider bore. Adjacent to the auger screw endof the spider is the auger screw bearing 53. This conveniently is ablind bearing hole in a bushing in the auger screw pilot bearing spiderand concentric therewith. A plastic bushing 54 fits in the auger screwhearing. A plastic bushing is preferred because such bushings areself-lubricating, are inert and nontoxic and non-metallic. Therefore, ifany portions of this plastic bushing are released into the granulation,it would be harmless to the user, and because self-lubricating, frictionis reduced and galling is minimized. Coneniently, the pilot bushing maybe of nylon or polytetraiiuoroethylene. A sheet of nylon can be cut on aa spiral so that a spiral-stepped bearing bushing of the proper size isobtained. In this bushing is pivoted the pilot shaft 55 of the augerscrew 47.

By having the auger screw supported at both ends, defiection of theauger screw is minimized and by using the clearances above mentioned offrom about 20 to 25 thousandths on the radius for a 2-inch radius screw,an extrusion system is formed with virutally no chance of the augerscrew rubbing on the auger sleeve with resultant galling, increasedfriction, burning of the granulation mass, and likelihood of metalfragments from the auger screw or auger sleeve being ripped loose andbeing released into the granulation.

In the modification shown in FIGURE 4, the discharge head is elongated.A section through the assembly along line 6-t5 is shown in FIGURE 6. Theelongated discharge head 43 has a corresponding shaped extrusion orificeplate 56. As shown in FIGURE 6, the extrusion orifice plate 56 is heldagainst the elongated discharge head 48 by a bracket 57 attached to theelongated discharge head by bolts 58.

The extrusion orifice plate has therein a plurality of stepped orifices59. As above mentioned, these stepped orifices consist of a larger holewhich extends part way through the orifice plate, and at the bottom ofwhich, extending the remaining way through the orific plate, is one ormore extrusion orifices 60.

Also shown in FIGURE 6 are drying air manifolds 61 to which drying airis supplied by air ducts 62. The inner surface of the drying airmanifolds has a number of dryface smoothness of the extruded strands.

ing air jets 63, through which warmed drying air is discharged onto thegranulation as it is extruded in strands through the extrusion orifices66. As above mentioned, a blast of hot air at this point gives a surfacehardening or case hardening to the strands which tends to prevent themfrom sticking to each other and renders them more readily handleable.The strands are allowed to drop upon a drying strip 64.

One convenient drying system is shown in FIGURE 7. Under the drying airmanifold 61, and in position to receive the strands as they are extrudedfrom the elongated discharge head, is a porous strip 65, such ascheesecloth. This strip is wide enough to receive the entire group ofextruded granules, for example, two feet, and is a long strip passingfrom a supply reel 65 over a pulley 67, under the extrusion head andover a drying box 68. This box conveniently is a stainless steel boxabout 70% of the upper surface of which is drilled out as orifices ofany convenient shape, and into which box is introduced drying airthrough a drying air duct 69. The drying air passes up through theperforated upper side of the drying box through the strip and dries thegranule strands on the surface of the strip. The strip then passes overanother pulley '70, then around a discharge pulley 71, to a take-up reel72. It is washed, if necessary, and reused. The

partially dried granules are dumped from the discharge pulley or by freefall into a drying hopper 73 which conveniently splits the granulestrands and passes them downward between respective pairs of four dryingscreens '74. Drying air is supplied to each of two drying air boxes 75which supply air through theouter two of the four drying screens. Theair, after passing through the granule mass, passes through the innerpair of the drying screens and out through an air discharge manifold 76.The granules, after passing between the drying screens, feed into agranule conveyor 77, which is a screw conveyor which discharges thedried granules for further processing and tablet manufacture.

Obviously, other forms of drying procedures may be used, but the oneshown is convenient and automatic and permits the continuous operationof the drying and extrusion steps. No manual handling of the granulestrands is required. If a cut-ofi knife is used, the granules may be cutto a length which is desired. Otherwise, the granules may be left inendless strands which are broken up through a power-driven screeningmechanism, such as a hammer mill, to sizes of granules which areconvenient for the particular tabletting operation contemplated. Becauseof the case hardening, the granules are comparatively firm, and infracturing release a minimum of fines.

Modifications of the screw extruder may be used. For instance, an augerscrew may be used which has two screw flights, or at least a partialsecond fight, so at the discharge end where heavier pressures areencountered the screw is symmetrical, and less unbalance of forces isencountered which reduces side thrust. Where a double screw is used, theend of the auger sleeve itself may be lined with plastic, and the endsof the screw flights can ride on this lining as the pilot bearing.

When colloidal matter is present, the extrusion orifice plate, or theauger screw, or both, may be electrically insulated from the remainderof the extruder, and connected to a source of low voltage directcurrent. Electroosmosis then causes the water in the mass to migrate tothe orifice plate or screw surface, and act as a lubricant to reducefriction, and at the orifice plate, to improve the sur- Usually,sulficient colloidal matter is present in the binder for electroosmosisto be helpful. The sign of the charge on the colloid determines thepolarity of the electrical connections.

Also, the extrusion press employed may be of the piston type instead ofthe auger screw type, and may be either vertical or horizontal. Althoughrevolving cutting knives are preferred for sectioning thestrands intogranules,

lit) other cutting means, such as cutting wires, may also be used.

The advantages of the novel apparatus of our invention are virtuallylegion, and provide a significant improvement and advancement in the artof making granule's for the production of tablets. The apparatusproduces a of agglomerates, and fines, which need no re-working. Due toan improved area-to-volume ratio, the granules produced by our novelapparatus may be dried more quickly than in the conventional wet granulating process. This results in a substantial decrease in manufacturingtime. The granules obtained by our invention show freedom from dust, areuniform in size, shape, density and color, exhibit free-flowing,nonbridging characteristics, are extremely tough and durable, and do notvary appreciably from batch to batch. This facilitates the production ofsubstantially correct size granules without rte-working. If the size ofthe granules as extruded and cut off is appropriately selected,commiuuting is not necessary.

Because of the free-flowing character, and the uniform densiy,,volumetric loading in a tabl'etting machine is simplified, and tabletsof comparatively uniform size, density, and weight, strength and color,are readily produced. For pharmaceutical purposes, uniformity in size,density and weight, is highly desirable.

Unexpectedly, it has been found that granules made by the novelapparatus of our invention require less lubricant for compression. Inaddition to a saving in material, this feature reduces dusting duringcompression and improves the uniformity of the color of the finishedtablet. The tablets formed from granules obtained by the novel apparatusof our invention quite unexpectedly show superior hardness, density'anddis ntegration properties. Capping and chipping during compression intotablet form are substantially reduced which, in turn, reduces losses dueto re-working and package return. Furthermore, the surface roughness ofthe tablets may be readily controlled, which is an aid in makingcoated'tablets. The number of pieces of equipment used and the man-hoursnecessary to handle a givenamount of material are enormously reduced bythe practice of the present invention. This, combined with the savingsin material obtained by the elimination of losses due to dusting,sticking, -etc., results in a substantial reduction in manu facturingcosts.

The versatility and efiiciency of the novel invention results inadditional savings of time and material which are not obvious at firstglance. Transfer and dust losses of material (which material may be ofvery high value) attributable both to the dry granulating and wetgranulating processes in current use, are completely eliminated.Moreover, the plasticized mass, which ordinarily causes material holdupby sticking to apparatus parts and then loss due to cleaning apparatusparts is confined to a single, self-cleaning auger sleeve. Accordingly,material loss is considerably less in the presentvinvention than inother granulating methods.

The standard pharmaceutical formulations currently used in theconventional wet granulating process may also be used in the novelinvention. Thus, an unexpected added advantage of the present inventionlies in thefact that sweeping formulation changes, which would requireextensive additional clinical investigation before being released forsale, are not necessary.

The novel present invention forms the basis for a means of combiningchemically incompatible ,materials. Test tablets exhibit between-granulebut not through-granule cleavage, thus indicating that the granules arenot unduly crushed or altered when compressed into tablets. As thereaction of chemically incompatible materials with one another in atablet must be at contacting surfaces, it follows that such reactionsare minimized by the use. of discrete granules which do not break upappreciably during compression into tablet form but remain particulateand separate.

- for a means of preparing mosaic tablets.

b d- This' characteristic of the granules produced by the novel presentinvention also forms the basis For example, a number of granulations,each having a different color due to innocuous, compatible dyes, areprepared by our process and-then simply mixed. By compression of thismixture, tablets are obtained having a mottled or mosaic appearancewhich is pleasing to the eye and most. attractive to children.

In another application, utilizing the characteristic toughness of thegranules, a distinctive tablet is made, the surface of which is sharplyinlaid with colored lines resembling a'very small scale'jigsaw puzzle.This tablet is made by dusting granules made by the invention with e aninnocuous dye, before compression. By polishing of the outer surfaces,the resulting network of lines outlines each granule on the suriace ofthe finished tablet. The exposing of grains, as described, is somewhatanalogous to the differential etching used in metallography to revealcrystal type and grain orientation. It should be noted that, incontradistinction to the efiect of fines" discussed j previously,dusting with dye does not inhibit compression.

Tablets having the jigsaw design are difiicult to counterfeit andprovide unmistakable tablet identification which would tend to reduce orprevent errors in dispensing and administering such tablets.

In some instances, it is desirable that medicaments be released in adesired order at a desired rate. By using the granules of the presentinvention, the individual granules may be coated with a delayingcoating, such as ethyl cellulose, or methyl cellulose,poly(vinylpyrrolidone), starch, shellac, or other release delayingmaterial, and the granules incorporated into the final tablets, orfilled into capsules. By a suitable choice of thickness of layer, and asuitable choice of the relative number of the granules to be coated, anydesired release program maybe achieved. Also, excellent sustainedrelease qualities are obtained by the use of suitable binders in thegranulation formula. The above coating materials, or glue, or gelatin,or a combination, are selected to give the desired release rate. Thetablets remain intact on ingestion, and because of high table to tabletuniformity, the release rate is consistent. Similarly, because thematerials being compressed are dry, eflervescents such as for example amixture of dry citric acid and dry sodium bicarbonate may be included inthe tablet, and the tablet processed and kept dry. As soon as the finaltablet is ingested, the moisture of the mouth and stomach causes therapid interaction of the citric acid and sodium bicarbonate with therelease of carbon dioxide which. causes the rapid disintegration of thetablets. By the inclusion of an etfervescent, the rapidity of the actionof the therapeutic agents in the tablet may be increased. Thus, it ispossible for tablets to be produced which have either an accelerated ora delayed release, or in part by suitable granulations being mixed, somecomponents may be released on an accelerated schedule, and others on adelayed schedule.

For delayed released materials, if a mottled tablet is used wherecertain of the granules, either in short segments or in longercylindrical strands, are compressed together, simple inspection willshow the relative proportions of each, and permit the operator, byinspection, to be certain that proper blending and mixing of thegranules forming the tablets is being achieved. Not only is amottled'configuration, including various colors, in the granulationsinteresting from the stand-point of a customer in having sales appeal,but the positive identification achieved is highly desirable as itprevents imitation, passing off or forgery. Even if the tablets are tobe coated with a sugar-coating, it is convenient that the contents havea mottled configuration in order that either the purchaser or thedispenser may, by cracking open the tablets, achieve positiveidentification.

- As an example, a dicalcium phosphate white blank from a powder havinga size of not less than 99.5% through a 200 US. Standard mesh sieve wasmixed with water, to form a crumb and placed in the hopper of themachine shown in FIGURE 4. When the agitated mixture was heated to 33C., and extruded at the same temperature, a throughput ofapproximately72 kilograms per hour was obtained. When the hopper washeated to about 60 C. and the jacket cooled to between 18 and 22 C., theextrusion rate was increased to 198 kilograms per hour. When the jackettemperature was decreased to 10. C., the extrusion rate was increased to288 kilo- "rams per hour, which approaches the free discharge rate ofthe screw. Hence, further improvements are theoretically impossiblewithout modifying the auger screw. The following table is typical of thetablets produced from the present screw-extruded compacted granulationand from a conventional wet granulation.

Table I Conventional Screw-Extruded Com- Granulation pacted GranulationTable Weight (Avg.

of 20) 1.4849 G1n 1.4917 Gm. Standard Deviation--- 0.0175 Gm (1.18%)"...0.0071 Gm. (0.48%). 20 Tablet Thickness (Avg. 0120) 0.214" 0.213".Standard Deviation... 0.00134 (0.63%) 0.00074 (0.35%). Tablet Hardness11.5 Kg. Strong-Cobb 17 Kg. Srrong-Cobb.

(Avg. of 20) (Crushing Strength). 3 Standard Deviation 1.28 Kg. (11.13%)1.55 Kg. (9.12%).

Tablet Friohility (Run on 10):

Percent Loss in 0.97 0.74.

weight after 100 falls. Percent Loss in 2 1.61%. q weight after 200 0falls.

extrusion orifices. The mixture was kept at about 60 C.,

and the cooling jacket at about 10 C. Two hundred cubic feet per minuteof air at 68 C. was blown through the case'hardening duct, which gave asurface hardening to the strands. The strands were dropped onto themoving belt, and 1,000 cubic feet per minute of air, at 68 C., was blownthough the cheesecloth. The moisture was cut from 7% to 3%, at whichpoint the product was snappable and could bereadily handled. The strandswere then dropped into the double-wall dryer of FIGURE 7 where air at120 C. was passed through for 2 hours, which cut the moisture content tonearly zero.

It was estimated that the extrusion pressure varied between 600 and2,000 lbs. per square inch at the face of the extrusion plate.

The extrusion blank after the drying step, was passed through aFitzpatrick screen, and broken to size such that about 15% would pass a1 2-mesh screen and be retained on a 16, 70% would pass a 16-mesh screenand be retained on a 40, 13.3% would pass a 40-mesh screen and beretained on a 200, and about 1.7% would pass a 200-mesh screen. Theblank granulation was mixed with an enzyme and then compacted to formtablets. Tablets were readily formed which had a hardness of 25kilograms, as tested on a Strong-Cobb hardness tester, the limit of thehardness test.

Usually it is desirable for small size pharmaceutical tablets to havefrom 0% to 20% pass a 12-mesh'screen, and be retained on a 16-mesh, andfrom 69 to 100 pass a 16, and be retained on a 40, and from 0% to 20%pass a 40, and be retained on a 200, and not more than 3% 7 stituents,in addition to the active therapeutic components,

are: an excipient or filler such as lactose or sucrose; a lubricant suchas magnesium stearate, calcium stearate, stearic acid, etc.; and abinder such as tragacanth, acacia, or a polyethylene glycol. These, aswell as a wide variety of other substances well known to those skilledin the art of preparing tablet granulations may be advantageouslyemployed in the process of this invention.

Inasmuch as the novel apparatus of this invention may be readilycontrolled within very narrow limits of temperature, it is particularlysuitable for the preparation of tablets containing pharmaceuticalcomponents which are sensitive to heat. Thus, it is possible to prepare,in

accordance with our invention, not only conventional tablets such asthose containing sulfonamides, digitalis, propylthiouracil and similartherapeutics but also tablets containing such labile pharmaceuticalingredients as vitamins, for example, Vitamins A, B, and D; alkaloidssuch as reserpine, morphine, hyoscyamine, and atropine; hormones such ascortisone; and antibiotics such as 6-demethyltetracycline,7-chlorotetracycline, tetracycline, penicillin and streptomycin.

It is to be understood that this invention is broadly adaptable to thepreparation of a wide variety of tablet granulations' in thepharmaceutical field, and it is intended that the broad, as well as thespecific, features and modifications of our novel invention be includedwithin the scope of our invention, as set forth in the appended claim. a

14. v a feed tube from the mixing hopper to the inletend of the aurgersleeve, means to rotate the auger screw, a discharge head having a rightangle, to deflect the discharged granulation to a downward path, anextrusion orifice plate, having a plurality ofsextrusion orificestherein, having a diameter of from about 0.01-inch to about0.05-inch,said orifices being of such a size that the addition orremoval of a single granule extruded therethrough will not appreciablyalter the size and dosage of a tablet produced therefrom, a coolingjacket for the 1 auger sleeve, whereby the plasticized mixture is cooledat the interface with the auger sleeve, thereby markedly increasingthroughput, a perforated vertical case hardening duct, a drying airinlet to supply hot air to said duct, an exhaust air duct, conveyormeans to remove the formed granules, said conveyor comprising a movingstrip of fabric, means to flow warmed air through the fabric, a dryinghopper in position to' receive the discharge from the fabric strip,foraminous areas in said drying hopper, means to blow warmed air throughsaid gear in the hopper, and conveying means to discharge the driedgranules.

References Qited by the Examiner UNITED STATES PATENTS CHARLES A.WILLMUTH, Primary Examiner,

M. O. WOLK, Examiner,

Locatelli 107-14.4

UNITED STATES PATENT OFFICE CERTIFICATE OF CGRRECTION Patent N003,177,820

April 13, 1965 Charles Arnold Pazar et ale Column 2, line 35, for"extruison" read extrusion line 40, for "the" read are column 12, line73, for "69" read 6O column 13, lines 5 and 8, for "table", eachoccurrence, read tablet Signed and sealed this 29th day of Ma 1966(SEAL) Attest:

ERNEST W. SWIDER EDWARD J. BRENNER Attesting Officer Commissioner ofPatents

